Abstract Over the past 40 years, the majority of the major etiological agents of newly emerged or identified infectious diseases in humans have been viruses, and most have been zoonoses caused by RNA viruses. The emergence or reemergence of pathogenic viruses are continuous threats to public health. Two recently emergent, zoonotic RNA viral pathogens come from the henipavirus genus within the paramyxovirus family: Hendra virus (HeV) and Nipah virus (NiV). HeV and NiV can cause a systemic and often fatal respiratory and/or neurological disease in at least 11 mammalian species including humans, with fatality rates ranging from 40-100%. There are no vaccines or therapeutics licensed for these viruses, highlighting an important unmet public health need. Due to their high potency and specificity, as well as their excellent clinical safety and efficacy record, monoclonal antibodies (mAbs) are an appealing platform for anti-viral therapeutics. With over 50 mAbs approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA), many of the manufacturing, formulation, and regulatory challenges of mAb drug development are well understood. The utility of antibodies, both naturally occurring and passively applied, has been evident for prevention and post- exposure treatment of infectious diseases for over a century. Three highly potent lead candidate therapeutic mAbs with anti-henipaviral activity are currently in hand, allowing development activities to begin immediately at the initiation of the CETR effort. Core B will focus on optimizing these candidates, down-selecting to the lead product format (a single mAb vs. a cocktail), and advancing the product towards clinical evaluation and development. To achieve these goals, we propose the following Specific Aims: 1. Optimize the individual in vivo potency of the 3 lead mAbs; 2. Evaluate the optimized mAbs in combinations to identify a lead product candidate; 3. Perform Investigational New Drug (IND)-enabling work. The 5 year effort will culminate with a final milestone of conducting a pre-IND meeting with the FDA.